Disease relevance of PYGM

• We have therefore undertaken studies to search for such mutations in six MEN type 1 tumors (four parathyroid tumors, one insulinoma, and one lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883 and PYGM centromerically and D11S449 and D11S913 telomerically [1].
• To clarify these issues, DNA extracted from archival tissue from 25 type I carcinoids, 4 type III carcinoids, and 2 neuroendocrine carcinomas was amplified by PCR, using primers for six polymorphic markers located on chromosome 11q13 (PYGM, D11S4946, and D11S913) and 11q14 (D11S916, D11S901, and D11S1365), for analysis of LOH [2].
• Infrequent (< or =12%) or absent LOH was detected at the remaining loci, including several loci commonly mutated in breast cancer (i.e., INT2, PYGM, and NM23) [3].
• Resolution of a mispaired secondary structure intermediate could account for a novel micro-insertion/deletion (387 insA/del 8 bp) in the PYGM gene causing McArdle's disease [4].
• DNA of blood and tumoral sections from two patients with adrenal myelolipoma were analyzed by examination of variable number of tandem repeats (VNTR) loci PYGM, D11S987, D11S480, and D11S449 on chromosome 11q13 and by complete direct DNA sequencing of all coding exons and splice junctions of the MEN-I gene [5].

High impact information on PYGM

• We performed linkage analysis in 31 multiplex BBS families and report significant linkage with two markers on chromosome 11q, PYGM and AFM164zf12 (D11S913) [6].
• Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's disease) [7].
• The myophosphorylase gene has been sequenced and assigned to chromosome 11, but the molecular basis of McArdle's disease is not known [7].
• Myophosphorylase deficiency (McArdle's disease) is one of the most common causes of exercise intolerance, muscle cramps, and recurrent myoglobinuria [7].
• Increased myophosphorylase a in malignant hyperthermia [8].

Chemical compound and disease context of PYGM

• They studied the oxidative capacity and lactate responses to maximal cycle exercise in eight patients with McArdle disease, seven single PYGM mutation carriers, and 11 healthy subjects [9].
• To determine if lactic acid is a critical mediator of metaboreflex activation in humans, we performed microelectrode recordings of MSNA in eight patients with myophosphorylase deficiency (McArdle's disease) who cannot metabolize intramuscular glycogen and do not generate lactic acid in exercising muscles [10].
• We measured purine degradation products of ATP in plasma after ischemic exercise in eight normal subjects, one patient with myophosphorylase deficiency (McArdle's disease), and one with carnitine palmityltransferase deficiency [11].
• Two different forms of myophosphorylase deficiency (McArdle's disease) can be distinguished through the presence or absence of the protein subunit corresponding to phosphorylase in muscle extracts analyzed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis [12].
• Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial [13].

Biological context of PYGM

• Localization of the photoreceptor gene ROM1 to human chromosome 11 and mouse chromosome 19: sublocalization to human 11q13 between PGA and PYGM [14].
• The human FAU gene maps to the long arm of chromosome 11 band q13, close to the PYGM locus [15].
• Loss of heterozygosity studies in MEN 1 and sporadic tumors suggest that the MEN1 gene encodes a tumor suppressor and have helped to narrow the location of the gene to a 600-kb interval between PYGM and D11S449 [16].
• Of these, two (137C7A, 137C7B) were derived from PYGM-containing BAC (bacterial artificial chromosome-137C7) sequences, one from INT2-containing cosmid sequences and the marker D11S4748, a (CA)20 repeat marker that was developed by us [17].
• We report two siblings with McArdle's disease who are both compound heterozygotes for two non-identical frameshift mutations in the PYGM gene; a previously reported 753 delA in exon 18 and a novel 387 insA/del 8 bp in exon 10 [4].

Anatomical context of PYGM

• Analysis of somatic cell hybrids suggested that the most likely localization of ROM1 is in the approximately 2-cM interval between human PGA (human pepsinogen A) and PYGM (muscle glycogen phosphorylase) [14].
• The genetic defect responsible for MEN-1 in three families was recently mapped to the long arm of chromosome II by linkage between the MEN-1 locus and the gene for skeletal muscle glycogen phosphorylase (PYGM) at 11q13 [18].
• The germinal center kinase gene and a novel CDC25-like gene are located in the vicinity of the PYGM gene on 11q13 [19].
• We analyzed leukocyte DNA from 32 patients with suspected McArdle's disease, 24 of whom had biochemically or histochemically proven myophosphorylase deficiency [20].
• Myophosphorylase gene transfer in McArdle's disease myoblasts in vitro [21].

Associations of PYGM with chemical compounds

• This homozygous T-to-C transition results in the replacement of a highly conserved tryptophan at amino acid position (aa) 797 with an arginine in the C-terminal domain of the PYGM protein [22].
• This homozygous C-to-A mutation results in the replacement of a highly conserved alanine at amino acid position 659 with an aspartic acid in the C-terminal domain of the myophosphorylase gene protein, near binding sites for pyridoxal phosphate and glucose [23].
• Expression of muscle-type phosphorylase in innervated and aneural cultured muscle of patients with myophosphorylase deficiency [24].
• Carnitine palmityl transferase deficiency may be more common than previously supposed, may be in part amenable to dietary therapy, can be easily distinguished from myophosphorylase deficiency, and may provide insight into the metabolism of fatty acids and ketone bodies as well as energy requirements of skeletal muscle [25].
• Activation of phosphorylase by cyclic AMP-dependent protein kinase was inhibited by antibodies to normal human myophosphorylase or by inhibitory protein to cyclic AMP-dependent protein kinase [26].

Other interactions of PYGM

• The locus for MEN1 is tightly linked to the marker PYGM on chromosome 11q13, and linkage analysis places the MEN1 gene within a 2-Mb interval flanked by the markers D11S1883 and D11S449 [16].
• TCN1, PGA, and PYGM did not yield any comigrating fragments and could not be physically linked on this PFGE map [27].
• Using highly polymorphic markers, we have narrowed the genetic region which contains the Best disease gene to the 10-cM region between markers D11S871 and PYGM [28].
• Two patients showed a defect of PPL in muscle, and were homozygous for the most common mutation associated with McArdle's disease, R49X in the muscle PPL gene (PYGM) [29].
• Linkage analysis of the Venezuelan reference pedigree places GSTP1 5 cM distal to PYGM and 4 cM proximal to FGF3 thereby providing a genetic marker half-way between these two loci [30].

Analytical, diagnostic and therapeutic context of PYGM

• We studied muscle of four patients; all lacked myophosphorylase activity, but myophosphorylase protein was demonstrated by immunodiffusion or gel electrophoresis [26].
• Results of the forearm ischaemic exercise test were positive in seven of seven patients with complete myophosphorylase deficiency; results of muscle biopsies were diagnostic in all patients [31].
• Therefore, immunoprecipitation is not a valid technique for differentiation of the variants of myophosphorylase deficiency, and another method, for example SDS-electrophoresis, should be applied [32].

References